Silyl-derivatives are widely used in synthetic organic chemistry to protect functional groups (e.g. alcohols, phenols, carboxylic acids, amines, acetylenes, and aromatic rings, etc.). See, for example, Greene et al. in Protecting Groups in Organic Synthesis, John Wiley and Sons, pp. 68 (1991) and Kocienski in Protecting Groups, Thieme, pp. 28 (1994). Silyl-derivatives are useful because they are inert to a wide range of synthetic organic chemistry conditions yet they can be removed (cleaved) under selective conditions (e.g. HF/pyridine, fluoride ion).
Linkers represent specialized forms of protecting groups used in solid-phase organic synthesis (SPOS). Linkers are solid-phase protecting groups, which allow attachment of a scaffold or template molecule to an insoluble support matrix. Attachment of the scaffold or template undergoing chemical modifications to an insoluble support provides a practical method to remove excess reagents and starting materials and spent reagents via extensive washing and filtration without loss of product. After suitable chemical modifications, the scaffold or template can be cleaved from the support matrix under selective conditions that will not alter the modified scaffold or template. Due to the explosion of interest and effort in combinatorial chemistry which utilizes SPOS, there is an increasing need for practical and selective linkers and reagents.
Polymeric silylating reagents have been used to attach alcohols on solid support. Farral; Frechet, J. Org. Chem., 41, 3877 (1976). Fyles; Leznoff, Can. J. Chem., 54, 935 (1976) used lithiation of the phenyl rings followed by trapping of aryl lithium intermediates with dialkyldichlorosilanes to prepare silylated resins. These types of silylated resins have been utilized for silyl ether based linkages by Chan; Huang, J. Chem. Soc., Chem. Commun., 909 (1995) and Randolph; McLure; Danishefsky, J. Am. Chem. Soc., 117, 5712 (1995). Maxson and Whitlock have also reported the preparation of arylsilane linkers and their use in cyclization reactions on solid-support (Maxson; Whitlock, "Silicon-Containing Solid Support Linker", poster #405 presented at the American Chemical Society, Division of Organic Chemistry, Orlando, Fla., Aug. 25-29, 1996.).
Diisopropylsilyloxy linkers bound to support through Si-O bonds have been developed to take advantage of the bulky isopropyl groups to stabilize the linkage. Routledge; Wallis; Ross; Fraser, Bioorg. Med. Chem. Lett., 5, 2059(1995), prepared a silyl derivatized CPG (controlled pore glass) silica that utilized 3'-hydroxy group as the point of attachment to the support for solid-phase oligonucleotide synthesis. Boehm; Showalter, J. Org. Chem., 61, 6498 (1996) developed a diisopropylarylsilyloxy linker for the traceless attachment during the synthesis of benzofurans. These linkers proved to be stable to strong basic conditions.
Several recent reports have utilized dimethylarylsilane linkers bound to support through Si-CH.sub.2 linkage with intervening heteroatoms in the spacer groups that allowed for the preparation of various substituted aromatic compound libraries by protodesilylation (ipso desilylation) or fluoride-mediated cleavage. One such application is in the synthesis of 1,4-benzodiazepine derivatives by Plunkett; Eliman, J. Org. Chem., 60, 6006 (1995). Similar dimethylarylsilane linkers containing intervening heteroatoms in the spacer chains have been reported by Chenera; Finkelstein; Veber, J. Am. Chem. Soc., 117, 11999 (1995), Han; Walker; Young, Tetrahedron Lett., 37, 2703 (1996), Chenera et. al. WO 95/16712, and Willems, Drug Discovery Today, 2, 214 (1997). A limitation in the aforementioned approaches is that scaffolds must first be attached to the silicon linker and then the linker is attached to the solid support. This requires a synthetic method for attaching the silicon linker to the scaffold to be developed for each scaffold.
Chenera and coworkers prepared silicon linkers of a resin-bound olefin with dimethylarylsilane derivatives via hydrosilylation (WO 98/17695). Similarly, Stranix et al (J. Org. Chem., 1997, 62, 6183-6186) prepared organosilicon protecting groups on (vinyl)polystyrene by hydrosilylation of a resin-bound olefin with dialkylchlorosilane derivatives. Woolard; Paetsch; ElIman (J. Org. Chem., 1997, 62, 6102-6103) recently reported a linkage strategy in which the arylsilyl group is attached to the support through an aliphatic tether. This arylsilyl linker can be activated by protodesilylation to provide a silyl chloride resin. Suspension polymerization of functional styrene monomers containing a pendant aryl silane was used for the preparation of silane resin which was then activated by protodesilylation [Stover; Lu,; Frechet, J. Polymer Bulletin, 25, 575-82 (1991)]. In the latter three cases, moisture sensitive silyl chlorides are necessary intermediates for loading of substrates.
Reactive and unstable silyl chlorides are commonly used in existing silicon-based linker approaches. Polymer-bound silyl-derivatives are typically produced by the reaction of silyl chlorides and the corresponding functionality. Polymer supported silyl chlorides have been reported by several workers. See Farral and Frechet (1976); Chang and Huang (1995); Randolph et al (1995); and Storer et al (1991).
Polymer supported silyl chlorides are beset by a number of limitations. For example, successful examples of silyl chlorides are largely restricted to silyl chlorides attached to polymer through an aromatic-silicon bond. Such polymer-bound silyl chlorides are prepared by aromatic ring lithiation and trapping with dialkyldichlorosilanes. These procedures are problematic due to potential cross-linking when highly activated, unhindered silanes are used (e.g., dimethyidichlorosilane); and the risk that the resulting resins are contaminated with lithium salts, which frequently cannot be extensively washed because washing promotes degradation of the Si-Cl moiety. Additionally, silyl chlorides leading to aromatic-silicon bonds have restricted utility due to their potential for competitive protodesilylation leading to undesirable cleavage of the linker.
Silyl chlorides have the further limitation of being reactive and unstable, making them poorly suited as commercial products. For example, reactions with moisture lead to hydrolysis of the silyl chloride to form a silanol (Si-OH). The silyl chloride's instability leads to poor shelf life. A further limitation associated with the use of polymer supported silyl chlorides is the difficulty associated with monitoring Si-Cl displacements using standard spectroscopic techniques.
A need thus currently exists for improved silicon-based linkers which overcome the disadvantages described above with regard to existing silicon-based linker technology.